This invention relates to synthetic and natural hormone-like peptides, to a method for their synthesis, and to their biological utility. More specifically, this invention relates to a new class of biologically active hormone-like peptides having a sequence of from 4-13 amino acids.
In copending application Ser. No. 136,670, filed Apr. 2, 1980, the disclosure of which is incorporated herein by reference, a hormone-like peptide having the following sequence is disclosed: EQU a-X.sub.1 -Arg-Val-X.sub.2 -Gln-Val-Gly-X.sub.3 -X.sub.4 -Pro-X.sub.5 -(Gly).sub.n (Asp).sub.m -c
wherein
a is a member of the group consisting of a free amino group and an acylated amino group; PA1 X.sub.1 is a member of the group consisting of Ser, Gln, Glu, and Pyr-Glu; PA1 X.sub.2 is a member of the group consisting of Lys and Ser; PA1 X.sub.3 is a member of the group consisting of Ser and Asn; PA1 X.sub.4 is a member of the group consisting of Ser, Gln and Lys; PA1 X.sub.5 is a member of the group consisting of Gln and Ser; PA1 c is a member of the group consisting of a free acid group and an acid amide group; PA1 n=0 or 1, and PA1 m=0 or 1, provided that when N=0, m=0; PA1 Pyr-Gln being pyrrolidyl glutamic acid. PA1 X.sub.1 -X.sub.7 are each, independently, an amino acid, PA1 a is a free amino group or an acylated amino group; PA1 c is a free acid group or an acid amide group; PA1 m, n, o, p, q, r, s, t and u are all integers of 0 or 1 with the proviso that m.gtoreq.n.gtoreq.o.gtoreq.p.gtoreq.q.gtoreq.r.gtoreq.s.gtoreq.t.gtoreq.u. PA1 X.sub.1 -X.sub.7 are each, independently of each other, an amino acid selected from the alpha-amino carboxylic acids, and pharmacologically active derivatives thereof, PA1 a is a member of the group consisting of a free amino group and an acylated amino group; PA1 c is a member of the group consisting of a free carboxylic acid group, a carboxylic acid amino group, and a carboxylic acid ester group; PA1 m, n, o, p, q, r, s, t and u are integers of 0 or 1, with the proviso that m.gtoreq.n.gtoreq.o.gtoreq.p.gtoreq.q.gtoreq.r.gtoreq.s.gtoreq.t.gtoreq.u.
The above-mentioned peptides, which have previously been extracted from brains of estivating lungfish Protopterus annectens (Owen) by the procedures described in Ser. No. 136,670, have been found to possess antimetabolic activity. For example, when injected intravenously into test animals, the peptide causes hypothermia, i.e., reduction in body temperature. It has also been found that the peptide causes the oxygen consumption and respiration rate of test animals (rats and mice) to be lowered. Using cultures of living cells from hamsters and liver cells from the rat, it has been found that protein biosynthesis and DNA-synthesis were lowered, causing a slowdown in cell division. Furthermore, the peptide has been found to be non-toxic since its effects are reversible. Tests also show that the peptide is non-species specific, i.e., it works in animals other than that which produces it.
As disclosed in the above-mentioned copending application, the peptide is extracted from the brains of estivating (sleeping), lungfish, Protopterus annectens (Owen). Such a species of lungfish is found in the Chad basin in Central Africa. However, since a large number of estivating lungfish must be sacrificed in order to yield a small amount of the peptide, there is a need for a process whereby the peptides can be synthesized in large quantities using off-the-shelf chemicals.
Efforts by the inventor to synthesize the 11-13 amino acid sequence peptide described above have not only been successful, but in addition, have led to the discovery of additional biologically-active peptides which are closely structurally related to the lungfish-derived peptides, but which have not been found in the lungfish. These synthetic hormone-like peptides have been shown to possess similar biological activity as the lungfish-derived peptides and, in some cases, greater activity.
Furthermore, biological activity, particularly DNA-biosynthesis in living cells, has been found in the synthetically derived peptide chains of as few as four amino acids.